Synthesis of rationally designed modified natural peptides from Boana cordobae and evaluation as multitarget agents against Alzheimer’s disease†

AVATANEO, LUISINA; SPINELLI, ROQUE; IVAN, SANCHIS; ÁLVARO, RIETMANN; ASCHEMACHER, NICOLAS; SIANO, ALVARO

Córdoba

Congreso; 6ta Reunión Internacional de Ciencias Farmacéuticas. Academia Nacional de Farmacia y Bioquimica; 2021

Academia Nacional de Farmacia y Bioquimica

Alzheimer'sdisease (AD) is a complex neurological disorder associated with different pathways,including cholinesterase enzymes (AChE and BChE), oxidative stress,biometals dyshomeostasis, among others. Because of this, a simultaneousmodulation is needed. Previously, we have reported the natural peptides BcI-1202 and BcI-1190, isolated from Boana cordobae’s skin, with inhibitoryactivity against both cholinesterases. The aim of this work was the in-silicodesign and chemical synthesis of substitution analogsof BcI-1202 and BcI-1190. For this, specific residues were changed for a tryptophanresidue to achieve the formation of π-π stacking interactions with catalyticresidues of cholinesterases. The results showed that the substitution analogsincrease the inhibitory activities against both cholinesterases, being theanalogs with two tryptophan insertions the most active. In this regard, forBChE, BcI-1202 (A3/A6 à W3/W6) showed a 30-fold decrement in IC50 values (200µM to6,50µM), while for BcI-1190 (S1/A4 à W1/W4) the decrease for IC50 was 66-fold (400µM to6,30µM). Concerning AChE, both modifications conferred potent inhibitoryactivity. On the other hand, the substitutions have given antioxidant andchelating capabilities. The tryptophan modifications allowed to obtainmultitarget peptides against therapeutic pathways of AD. We propose thisstrategy as an innovative tool to increase or confer bioactivity.